Of the many phenylpropylamines which show analgesic activity, the two most important are methadone and propoxyphene. The optically active alpha-dextro stereoisomer of propoxyphene is the only stereoisomer of propoxyphene which possesses analgesic properties. It is commonly used in its hydrochloride salt form which is a bitter, white crystalline powder freely soluble in water and soluble in alcohol. Its chemical name is .alpha.-d-1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane hydrochloride and is sold under several different trademarks including, for example, DARVON, DOLENE, and SK-65. The napsylate salt, i.e., the naphthalene sulfonate, is also used in many drug forms. It has previously been made from the hydrochloride salt.
Preparation of d-propoxyphene hydrochloride was first described by A. Pohland and H. R. Sullivan at J. Am. Chem. Soc., Volume 75, pp. 4458(1953). Therein, the authors disclosed a synthesis involving several stages, (1) preparation of an aminoketone called .beta.-dimethylaminobutrophenone by addition of the secondary amine to phenylpropenyl ketone; (2) a Grignard reaction of the amino ketone with benzylmagnesium chloride to yield the amino, hydrochloride-carbinols described as .alpha.-(75%) and .beta.-(15%) 4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol hydrochloride (sometimes hereinafter referred to as d-oxyphene hydrochloride); and (3) acylation of the .alpha.-amino carbinol hydrochloride by addition of an equal weight of propionic anhydride and five times that weight of pyridine and heating to reflux for several hours. Note the following reaction formula: ##STR1##
After cooling to recover the crude product, it was purified by two recrystallizations from methanol-ethyl acetate solution resulting in a yield of 70%.
Although this work confirmed that the .alpha. and not the .beta.-diastereoisomers of propoxyphene gave rise to analgesic activity, it was still necessary to determine which of the optical forms of the .alpha.-diastereoisomer, i.e. .alpha.-d(+) or .alpha.-l(-), was responsible for the analgesic activity. Accordingly, Pohland and Sullivan reported in the J. Am. Chem. Soc., Volume 77, pp. 3400 (1955) their work on resolution of .alpha.-dl-4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol by fractional crystallization of its d-camphorsulfonic acid salt. From the respective .alpha.-d and .alpha.-l carbinol d-camphorsulfonic salts the optically active hydrochloride salts were prepared. The .alpha.-d-hydrochloride was acylated using propionic anhydride and triethylamine, while the .alpha.-l hydrochloride was acylated using propionic anhydride and pyridine. It was therein found that only the .alpha.-d stereoisomer gave the analgesic response. However, final purification of the hydrochloride salt required additional HCl and three recrystallizations and with yields of less than about 70%.
In 1963, Pohland, Peters and Sullivan reported in the J. Org. Chem., Vol. 28, pp. 2483, an alternative synthetic route for .alpha.-d-propoxyphene hydrochloride. Working backwards from the desired optically active isomer of propoxyphene by its hydrolysis and dehydration to stilbene, followed by ozonization of the stilbene, the authors discovered good yield of (-)-.beta.-dimethylamino-.alpha.-methylpropiophenone. This optically active amino ketone was found to be surprisingly stable in salt form thus permitting its use as a starting material for a stereo selective synthesis of .alpha.-d-propoxyphene. Racemic .beta.-dimethylamino-.alpha.-methylpropiophenone was resolved by crystallization of the dibenzoyl tartrate salts from acetone solution. The use of dibenzoyl-(-)-tartaric acid yielded the insoluble salt having (-)-.beta.-dimethylamino-.alpha.-methylpropiophenone, while the use of the (+) tartaric acid yielded the salt having the (+) amino ketone isomer.
It is of interest that according to this reported synthesis, it was the (-) isomer of .beta.-dimethylamino-.alpha.-methylpropiophenone, which when liberated from its (-) tartrate salt by Grignard reaction with benzylmagnesium chloride provided good yields of the (+) or (d) isomer .alpha.-1,2-diphenyl-3-methyl-4-dimethylamino-2-butanol which of course is the carbinol precursor for .alpha.-d-propoxyphene. The reported yields were 69%. The acylation was accomplished as had been previously reported, i.e., by means of propionic anhydride in either triethylamine or pyridine.
In 1978, Hungarian Pat. No. 14,441 disclosed a synthesis of .alpha.-d-propoxyphene employing the above-described method except that (1) the (+) tartaric acid was employed in the resolution of the racemic .beta.-dimethylamino-.alpha.-methylpropiophenone and (2) the acylation was accomplished by reacting triethylamine in chloroform, propionyl chloride and the carbinol rather than propionyl anhydride and the carbinol hydrochloride. Still the product was precipitated in ether and required an amine catalyst.
Most recently, U.S. Pat. No. 4,661,625 disclosed a synthetic method involving acylation of the carbinol (d-oxyphene) with propionyl chloride and thionyl chloride in dichloromethane. The yield of d-propoxyphene hydrochloride was improved to at least 76%, but use of the toxic additive thionyl chloride was required to get to that level. In addition, methylene chloride or another chlorinated solvent was required. Chlorinated impurities resulted and caused difficulties in purification.
However, a method that provides even higher yields of d-propoxyphene and its salts and doesn't require toxic and/or hazardous additives and solvents has long been highly desired. It is an object of the present invention to provide a means of producing d-propoxyphene in high yields without the need for amines or chlorinated solvents. It is a further object to provide methods of producing the hydrochloride and napsylate salts of d-propoxyphene in higher yields than previously obtainable.